The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome |
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Authors: | Taxman Debra J Holley-Guthrie Elizabeth A Huang Max Tze-Han Moore Chris B Bergstralh Daniel T Allen Irving C Lei Yu Gris Denis Ting Jenny Pan-Yun |
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Institution: | Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. |
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Abstract: | ASC/PYCARD is a common adaptor for a diverse set of inflammasomes that activate caspase-1, most prominently the NLR-based inflammasome. Mounting evidence indicates that ASC and these NLRs also elicit non-overlapping functions, but the molecular basis for this difference is unclear. To address this, we performed microarray and network analysis of ASC shRNA knockdown cells. In pathogen-infected cells, an ASC-dependent interactome is centered on the mitogen-activated protein kinase (MAPK) ERK and on multiple chemokines. ASC did not affect the expression of MAPK but affected its phosphorylation by pathogens and Toll-like receptor agonists via suppression of the dual-specificity phosphatase, DUSP10/MKP5. Chemokine induction, DUSP function, and MAPK phosphorylation were independent of caspase-1 and IL-1β. MAPK activation by pathogen was abrogated in Asc(-/-) but not Nlrp3(-/-), Nlrc4(-/-), or Casp1(-/-) macrophages. These results demonstrate a function for ASC that is distinct from the inflammasome in modulating MAPK activity and chemokine expression and further identify DUSP10 as a novel ASC target. |
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Keywords: | Chemokines Dual-specificity Phosphoprotein Phosphatase Inflammation MAP Kinases (MAPKs) Toll-like Receptors (TLRs) Inflammasome NLR Porphyromonas gingivalis ASC/PYCARD |
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